vldl hydrolysis by hepatic lipase regulates pparδ transcriptional responsesvldl由肝脂肪酶水解调节pparδ转录反应.pdfVIP

VLDL Hydrolysis by Hepatic Lipase Regulates PPARd Transcriptional Responses 1,2 1,3 4 5 1 Jonathan D. Brown , Eric Oligino , Daniel J. Rader , Alan Saghatelian , Jorge Plutzky * 1 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2 VA Boston Healthcare, West Roxbury, Massachusetts, United States of America, 3 Division of Cardiology, Yale-New Haven Hospital, New Haven, Connecticut, United States of America, 4 Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 5 Department of Chemistry, Harvard University, Cambridge, Massachusetts, United States of America Abstract Background: PPARs (a,c,d) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown. Methods/Principal Findings: Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (.HDLLDL, IDL) to activate PPARd preferentially over PPARa or PPARc, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARd in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARd target genes, including adipoc